Fatigue continues to be a major problem for many people with HIV/AIDS, even when their health is otherwise stable or restored by antiretroviral medication. Fatigue in HIV is associated with disability and diminished life satisfaction, and is a significant barrier for those who consider returning to work. While earlier in the epidemic, fatigue was attributed to the virus and concomitant opportunistic infections, more recently it seems that the otherwise life-extending antiretrovirals also play a role. Previous research by our group and others has demonstrated that fatigue in patients with HIV/AIDS is responsive to psychostimulants such as dextroamphetamine and methylphenidate. However, access to these drugs is limited by physician reluctance to prescribe them, dose escalation is often necessary, and for patients with substance abuse histories they are largely contraindicated. Consequently, there remains a significant unmet need for an effective treatment for HIV-associated fatigue. We propose to conduct a 4-week placebo controlled double blind trial of modafinil for HIV+ patients with clinically significant fatigue, followed by an 8-week maintenance phase for modafinil responders. Modafinil is approved for the treatment of narcolepsy, but its use has been extended to treat fatigue and excessive daytime sleepiness in other patient groups with neurological disease or depression, and findings have been positive. We plan to enter 120 patients with the expectation of having at least 100 study completers. The major aims concern modafinil efficacy for fatigue compared to placebo, safety in terms of effects on immunologic/virologic measures, and impact on depressive symptoms when present at baseline.